It is known that several representatives of amidoxime derivatives of the formula (I) ##STR3## are useful for the treatment of diabetic angiopathy which is practically unique to the present. Other amidoxime derivatives show a blood pressure lowering action, too and an alpha-blocking effect may also be observed (British patent specification No. 1,582,029; U.S. Pat. Nos. 4,187,220 and 4,308,399). The possibility of the use of these compounds as therapeutic drugs demands an economical preparation which can be carried out on an industrial scale.
It is known that O-substituted derivatives of oximes are usually prepared by employing alkylating agents (Houben Weyl Vol. X/4, pages 217 to 220 (1968)). The O-substituted amidoximes according to the present invention have been prepared by reacting amidoximes with epoxides (or their functional equivalents), i.e. with the epoxy compounds of the formula (IV) ##STR4## or with 1-halo-2-hydroxy-3-propanamines of the formula (III) ##STR5## or with 3-hydroxyazetidine salts of the formula (V) ##STR6## respectively. Protic solvents such as water, methanol, ethanol or mixtures of water with a water-immiscible solvent, e.g. benzene were used as solvents in these reactions. The final products were isolated by extraction (sometimes after evaporation), the extract was washed several times with a concentrated alkaline solution and after solvent change it was acidified by alcoholic hydrochloric acid and carefully crystallized. The hydrochlorides of the products were obtained in yields between 6% and 50% in this way.
On reproduction and scale increase of these reactions it has surprisingly been found that the amidoximes of the formula (II) ##STR7## could not completely be transformed. After a reaction of about 60 to 70%, the reaction stopped and both an increase in the reaction temperature or use of an excess of reactant enhanced the amount of tarry side products which inhibited the isolation of the product.